1. Field of the Invention
The present invention relates generally to the modulation of neovascularization and/or the growth of collateral arteries or other arteries from preexisting arteriolar connections.
2. Related Art
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including any manufacturer's specifications, instructions, etc.) are hereby incorporated herein by reference; however, there is no admission that any document cited is indeed prior art as to the present invention.
In the treatment of subjects with arterial occlusive diseases most of the current treatment strategies aim at ameliorating their effects. The only curative approaches involve angioplasty (balloon dilatation) or bypassing surgery. The former carries a high risk of restenosis and can only be performed in certain arterial occlusive diseases, like ischemic heart disease. The latter is invasive and also restricted to certain kinds of arterial occlusive diseases. There is no established treatment for the enhancement of neovascularization and/or collateral growth.
Vascular growth in adult organisms proceeds via two distinct mechanisms, sprouting of capillaries (angiogenesis) and in situ enlargement of preexisting arteriolar connections into true collateral arteries (Schaper, J. Collateral Circulation—Heart, Brain, Kidney, Limbs. Boston, Dordrecht, London: Kluwer Academic Publishers; 1993). Recent studies have disclosed mechanisms leading to angiogenesis with vascular endothelial growth factor (VEGF) as a major component (Tuder, J. Clin. Invest. 95 (1995), 1798-1807; Plate, Nature 359 (1992), 845-848; Ferrara, Endocrine Reviews 13 (1992), 18-42; Klagsbrun, Annu. Rev. Physiol. 53 (1991), 217-239; Leung, Science 246 (1990), 1306-1309). This specific endothelial mitogen is upregulated by hypoxia and is able to promote vessel growth when infused into rabbit hindlimbs after femoral artery excision (Takeshita, J. Clin. Invest. 93 (1994), 662-670; Bauters, Am. J. Physiol. 267 (1994), H1263-H1271). These studies however did not distinguish between capillary sprouting, a mechanism called angiogenesis, and true collateral artery growth. Whereas VEGF is only mitogenic for endothelial cells, collateral artery growth requires the proliferation of endothelial and smooth muscle cells and pronounced remodeling processes occur (Schaper, J. Collateral Circulation—Heart, Brain, Kidney, Limbs. Boston, Dordrecht, London: Kluwer Academic Publishers; 1993; Jakeman, J. Clin. Invest. 89 (1992), 244-253; Peters, Proc. Natl. Acad. Sci. USA 90 (1993), 8915-8919; Millauer, Cell 72 (1993), 835-846; Pasyk, Am. J. Physiol. 242 (1982), H1031-H1037). Furthermore mainly capillary sprouting is observed in ischemic territories for example in the pig heart or in rapidly growing tumors (Schaper, J. Collateral Circulation—Heart, Brain, Kidney, Limbs. Boston, Dordrecht, London: Kluwer Academic Publishers; 1993; Plate, Nature 359 (1992), 845-848; Bates, Curr. Opin. Genet. Dev. 6 (1996), 12-19; Bates, Curr. Opin. Genet. Dev. 6 (1996), 12-19; Görge, Basic Res. Cardiol. 84 (1989), 524-535). True collateral artery growth, however, is temporally and spacially dissociated from ischemia in most models studied (Schaper, J. Collateral Circulation—Heart, Brain, Kidney, Limbs. Boston, Dordrecht, London: Kluwer Academic Publishers; 1993; Paskins-Hurlburt, Circ. Res. 70 (1992), 546-553). Other or additional mechanisms as those described for angiogenesis in ischemic territories are therefore needed to explain collateral artery growth. From previous studies it is known that these collateral arteries grow from preexisting arteriolar connections (Schaper, J. Collateral Circulation—Heart, Brain, Kidney, Limbs. Boston, Dordrecht, London: Kluwer Academic Publishers; 1993).
However, while agents such as VEGF and other growth factors are presently being employed to stimulate the development of angiogenesis after arterial occlusion, such agents are not envisaged as being capable of modulating the growth of preexisting arteriolar connections into true collateral arteries.
Thus, the technical problem of the present invention is to provide pharmaceutical compositions and methods for the modulation of neovascularization and/or the growth of collateral arteries and/or other arteries from preexisting arteriolar connections.